Type I interferon, including interferon α (IFNα) and interferon β (IFNβ), are the most important factors of innate immunity responsible for protection of an organism from a viral infection and tumor growth. These cytokines perform their signal function by interacting with one receptor on a cell surface. The receptor is a heterodimer consisting of two chains IFNAR1 and IFNAR2. The interaction of interferons with the receptor results in activation of biochemical chains, starting with activation of Janus-kinases Tyk2 and Jak1 that provide phosphorylation of signal transducers and transcription activators Stat1 and Stat2. The latter molecules provide transcription of interferon-stimulated genes encoding antiviral effector proteins.
Interferon signals are powerful stimuli altering homeostasis, function and division of various interferon receptor-containing cells in the organism. Uncontrolled interaction of interferon molecules with receptors may have a toxic, damaging action on cells of the immune system and the whole organism. For example, a defect in the interferon-signaling pathway results in the development of pathology, such as systemic lupus erythematosus. In this connection, the intensity of interferon signaling is under strict control involving various mechanisms and, first of all, modulation/reduction in the density of interferon receptors on a cell surface (Coccia E. M., Uze G., Pellegrini S. (2006) Negative regulation of type I interferon signaling: facts and mechanisms. Cell Mol Biol (Noisy-le-grand) 52: 77-87). This physiological mechanism includes phosphorylation, ubiquitination, endocytosis, and subsequent degradation of a receptor subunit IFNAR1 in cell proteasomes (Kumar K. G., Krolewski J. J., Fuchs S. Y. (2004) Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. J Biol. Chem 279: 46614-46620).
Viruses use this physiological mechanism for their own benefit by reducing the intensity of interferon signaling, including by means of degradation of interferon receptors. The action of pathogens can include a directed suppression of interferon receptors with viral proteins. For example, hepatitis B virus reduces the density of interferon receptors with protein X (Cho I. R., Oh M., Koh S. S., Malilas W., Srisuttee R., Jhun B. H., Pellegrini S., Fuchs S. Y., Chung Y. H. Hepatitis B virus X protein inhibits extracellular IFN-α-mediated signal transduction by downregulation of type I IFN receptor. Int J Mol Med. 2012 April; 29(4):581-6. doi: 10.3892/ijmm.201.2.879. Epub 2012 Jan. 3). Other viruses, including herpes viruses, reach an effect of a reduction in the density of interferon receptors through cellular stress induced by the viruses (Liu J., HuangFu W. C., Kumar K. G. et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe 2009; 5:72-83). For example, herpes simplex viruses are able to reduce effectively the density of interferon receptors by degradation of their first subunit IFNAR1. (Qian j., Zheng H., Huangfu W. C., Liu j., Carbone C. J., Lou N. A., Baker D. P., Fuchs S. Y. Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. PLoS Pathog. 2011 June; 7(6):e1002065. doi: 10.1371/journal.ppat.1002065. Epub 2011 Jun. 9). It is known that the herpes virus family is represented by eight types of herpes viruses causing in humans diseases of various severity. The diseases are characterized in that the viruses are in a human body in their latent state.
A similarity in the genome structure of various herpes viruses provides common mechanisms of blocking interferon signaling.
Another example of viral modulation of interferon receptors in a viral infection is a disturbance in the balance between the interferon receptor subunits in papillomavirus oncogenesis in women (Tirone N. R., Peghini B. C., Barcelos A. C., Murta E. F., Michelin M. A. Local expression of interferon-alpha and interferon receptors in cervical intraepithelial neoplasia. Cancer Immunol Immunother. 2009 December: 58(12):2003-10. doi:10.1007/s00262-009-0707-6. Epub 2009 Apr. 18. PubMed PMID: 19381629).
Thus, acute and chronic viral infections are accompanied by interferon system suppression caused, inter alia, by accelerated degradation of interferon receptors (Qian J., Zheng H., Huangfu W. C., Liu J., Carbone C. J., Leu N. A., Baker D. P., Fuchs S. Y. Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. PLoS Pathog. 2011 June; 7(6):e1002065. doi: 10.1371/journal.ppat.1002065. Epub 2011 Jun. 9; 2008 Jun. 15; 197(1):54-62).
Chronic intoxications of an organism, for example, tobacco smoking, lead to a reduction in the density of interferon receptors in respiratory tract cells, thus resulting in an increased incidence of viral diseases in smokers and, probably, in a risk of lung cancer (Huang Fu W. C., Liu J., Harty R. N., Fuchs S. Y. Cigarette smoking products suppress anti-viral effects of Type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS Lett. 2008 Sep. 22; 582(21-22):3206-10; Picaud S, Bardot B, De Maeyer E, Seif I. Enhanced tumor development in mice lacking a functional type I interferon receptor. J Interferon Cytokine Res. 2002 April; 22(4):457-62).
Currently, diseases accompanied by interferon system suppression are treated with recombinant (exogenous) interferon drugs. In that case, a reduced sensitivity of damaged cells to exogenous interferon is compensated with high doses of a drug. This results in toxic effects caused by interferon therapy, in particular, with the development of depressive syndromes (Patten S. B. Psychiatric side effects of interferon treatment. Curr Drug Saf. 2006 May; 1(2):143-50. Review. PubMed PMID: 18690925). Resistance to the therapy is mainly determined by a reduced expression of interferon receptors. For example, a reduced level of synthesis of the mRNA subunit of interferon receptor IFNAR1 observed in multiple sclerosis results in a reduced efficiency of therapy with interferon β (Serana F., Sottini A., Ghidini C., Zanotti C., Capra R., Cordioli C., Caimi L., Imberti L. Modulation of IFNAR1 mRNA expression in multiple sclerosis patients. J Neuroimmunol. 2008 Jun. 15; 197(1):54-62).
The same is observed in interferon therapy of chronic viral diseases. Virus-infected cells, losing a certain amount of interferon receptors, become non-sensitive to interferon therapy. For example, an effect of therapy with interferon-alpha in hepatitis B is often short-lived, and the disease passes to the stage of exacerbation accompanied by a rise in viral genome copies in the human blood. This means that a part of virus-infected cells in the organism did not respond to interferon therapy. For the same reason, interferon drugs do not heal a chronic infection caused by various herpes viruses (Kroeker A. L., Coombs K. M. Systems biology unravels interferon responses to respiratory virus infections. World J Biol. Chem. 2014 Feb. 26; 5(1):12-25. doi: 10.4331/wjbc.v5.i1.12. Review. PubMed PMID: 24600511; PubMed Central PMCID: PMC3942539); (Eron L. J., Toy C., Salsitz B., Scheer R. R., Wood D. J., Nadler P. I. Therapy of genital herpes with topically applied interferon. Antimicrob Agents Chemother. 1987 July; 31(7):1137-9. PubMed PMID: 3310870; PubMed Central PMCID: PMC174885).
The present inventors have unexpectedly found that an effective method for treating diseases accompanied by a reduced sensitivity of cells to interferon is a therapy directed to an increase in the density of interferon receptors on a cell surface. In this case, sensitization of cells to endogenous interferon signals can result in a therapeutic effect without the use of the preparations of a recombinant interferon or can provide a reduction of its therapeutic doses.
Currently, there is no agent capable of recovering or increasing the density of interferon receptors in case of their degradation in various pathological conditions. The present inventors have unexpectedly found that glutaryl histamine leads to an increased synthesis of the messenger RNAs of interferon receptors and an increased density of the receptors as such on a cell surface. Thus, glutaryl histamine is capable of recovering and/or increasing the density of interferon receptors on a cell surface, which makes this agent promising for prevention or treatment of a number of diseases. This agent can be used as monotherapy of viral diseases to achieve an effect of an increased sensitivity of cells to a low level of endogenous interferon because of a rise in the density of interferon receptors on a cell surface. In addition, glutaryl histamine can be used in complex therapy with interferon drugs to increase a response of immunosuppressed cells to an exogenous interferon.